Abstract
Renal fibrosis is considered as the pathway of almost all kinds of chronic kidney diseases (CKD) to the end stage of renal diseases (ESRD). Ganoderic acid (GA) is a group of lanostane triterpenes isolated from Ganoderma lucidum, which has shown a variety of pharmacological activities. In this study we investigated whether GA exerted antirenal fibrosis effect in a unilateral ureteral obstruction (UUO) mouse model. After UUO surgery, the mice were treated with GA (3.125, 12.5, and 50 mg· kg−1 ·d−1, ip) for 7 or 14 days. Then the mice were sacrificed for collecting blood and kidneys. We showed that GA treatment dose-dependently attenuated UUO-induced tubular injury and renal fibrosis; GA (50 mg· kg−1 ·d−1) significantly ameliorated renal disfunction during fibrosis progression. We further revealed that GA treatment inhibited the extracellular matrix (ECM) deposition in the kidney by suppressing the expression of fibronectin, mainly through hindering the over activation of TGF-β/Smad signaling. On the other hand, GA treatment significantly decreased the expression of mesenchymal cell markers alpha-smooth muscle actin (α-SMA) and vimentin, and upregulated E-cadherin expression in the kidney, suggesting the suppression of tubular epithelial-mesenchymal transition (EMT) partially via inhibiting both TGF-β/Smad and MAPK (ERK, JNK, p38) signaling pathways. The inhibitory effects of GA on TGF-β/Smad and MAPK signaling pathways were confirmed in TGF-β1-stimulated HK-2 cell model. GA-A, a GA monomer, was identified as a potent inhibitor on renal fibrosis in vitro. These data demonstrate that GA or GA-A might be developed as a potential therapeutic agent in the treatment of renal fibrosis.
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References
Zeisberg M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol. 2010;21:1819–34.
Boor P, Ostendorf T, Floege J. Renal fibrosis: novel insights into mechanisms and therapeutic targets. Nat Rev Nephrol. 2010;6:643–56.
Farris AB, Colvin RB. Renal interstitial fibrosis: mechanisms and evaluation. Curr Opin Nephrol Hypertens. 2012;21:289–300.
De Nicola L, Minutolo R. Worldwide growing epidemic of CKD: fact or fiction? Kidney Int. 2016;90:482–4.
Levin A, Tonelli M, Bonventre J, Coresh J, Donner JA, Fogo AB, et al. Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy. Lancet. 2017;390:1888–917.
Zhang L, Wang F, Wang L, Wang W, Liu B, Liu J, et al. Prevalence of chronic kidney disease in China: a cross-sectional survey. Lancet. 2012;379:815–22.
Nordio M, Limido A, Maggiore U, Nichelatti M, Postorino M, Quintaliani G, et al. Survival in patients treated by long-term dialysis compared with the general population. Am J Kidney Dis. 2012;59:819–28.
Webster AC, Nagler EV, Morton RL, Masson P. Chronic kidney disease. Lancet. 2017;389:1238–52.
Breyer MD, Susztak K. The next generation of therapeutics for chronic kidney disease. Nat Rev Drug Discov. 2016;15:568–88.
Chen DQ, Feng YL, Cao G, Zhao YY. Natural products as a source for antifibrosis therapy. Trends Pharmacol Sci. 2018;39:937–52.
Hsu CL, Yen GC. Ganoderic acid and lucidenic acid (Triterpenoid). Enzymes. 2014;36:33–56.
Gill BS, Navgeet, Kumar S. Ganoderma lucidum targeting lung cancer signaling: a review. Tumor Biol 2017;39:1010428317707437. https://doi.org/10.1177/1010428317707437.
Zhong D, Wang H, Liu M, Li X, Huang M, Zhou H, et al. Ganoderma lucidum polysaccharide peptide prevents renal ischemia reperfusion injury via counteracting oxidative stress. Sci Rep 2015;5:16910.
He J, Sun Y, Jia Y, Geng X, Chen R, Zhou H, et al. Ganoderma triterpenes protect against hyperhomocysteinemia induced endothelial-mesenchymal transition via TGF-beta signaling inhibition. Front Physiol. 2019;10:192.
Su L, Liu L, Jia Y, Lei L, Liu J, Zhu S, et al. Ganoderma triterpenes retard renal cyst development by downregulating Ras/MAPK signaling and promoting cell differentiation. Kidney Int. 2017;92:1404–18.
Zhong D, Xie Z, Huang B, Zhu S, Wang G, Zhou H, et al. Ganoderma lucidum polysaccharide peptide alleviates hepatoteatosis via modulating bile acid metabolism dependent on FXR-SHP/FGF. Cell Physiol Biochem. 2018;49:1163–79.
Lu J, Qin JZ, Chen P, Chen X, Zhang YZ, Zhao SJ. Quality difference study of six varieties of ganoderma lucidum with different origins. Front Pharmacol. 2012;3:57.
Jiang J, Grieb B, Thyagarajan A, Sliva D. Ganoderic acids suppress growth and invasive behavior of breast cancer cells by modulating AP-1 and NF-kappaB signaling. Int J Mol Med. 2008;21:577–84.
Zhang X, Xiao C, Liu H. Ganoderic acid A protects rat H9c2 cardiomyocytes from hypoxia-induced injury via up-regulating miR-182-5p. Cell Physiol Biochem. 2018;50:2086–96.
Cao FR, Feng L, Ye LH, Wang LS, Xiao BX, Tao X, et al. Ganoderic acid A metabolites and their metabolic kinetics. Front Pharmacol. 2017;8:101.
Lin DM, Wang SZ, Luo HJ, Lin ZX, Lin SQ. Rapid separation of ganoderic acid from the extraction by-products of Ganoderma lucidum. Fujian Med J. 2018;40:135–8.
Chevalier RL, Forbes MS, Thornhill BA. Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy. Kidney Int. 2009;75:1145–52.
Bao YW, Yuan Y, Chen JH, Lin WQ. Kidney disease models: tools to identify mechanisms and potential therapeutic targets. Zool Res. 2018;39:72–86.
Jia Y, He J, Wang L, Su L, Lei L, Huang W, et al. Dapagliflozin aggravates renal injury via promoting gluconeogenesis in db/db mice. Cell Physiol Biochem. 2018;45:1747–58.
Wang W, Li F, Sun Y, Lei L, Zhou H, Lei T, et al. Aquaporin-1 retards renal cyst development in polycystic kidney disease by inhibition of Wnt signaling. FASEB J. 2015;29:1551–63.
Wang W, Geng X, Lei L, Jia Y, Li Y, Zhou H, et al. Aquaporin-3 deficiency slows cyst enlargement in experimental mouse models of autosomal dominant polycystic kidney disease. FASEB J. 2019. https://doi.org/10.1096/fj.201801338RRR.
Pillai TG, John M, Sara Thomas G. Prevention of cisplatin induced nephrotoxicity by terpenes isolated from Ganoderma lucidum occurring in southern parts of India. Exp Toxicol Pathol. 2011;63:157–60.
Lan HY. Smad7 as a therapeutic agent for chronic kidney diseases. Front Biosci. 2008;13:4984–92.
Watanabe H, de Caestecker MP, Yamada Y. Transcriptional cross-talk between Smad, ERK1/2, and p38 mitogen-activated protein kinase pathways regulates transforming growth factor-beta-induced aggrecan gene expression in chondrogenic ATDC5 cells. J Biol Chem. 2001;276:14466–73.
Hung TW, Tsai JP, Lin SH, Lee CH, Hsieh YH, Chang HR. Pentraxin 3 activates JNK signaling and regulates the epithelial-to-mesenchymal transition in renal fibrosis. Cell Physiol Biochem. 2016;40:1029–38.
Stambe C, Atkins RC, Tesch GH, Masaki T, Schreiner GF, Nikolic-Paterson DJ. The role of p38alpha mitogen-activated protein kinase activation in renal fibrosis. J Am Soc Nephrol. 2004;15:370–9.
Feng Y, Ren J, Gui Y, Wei W, Shu B, Lu Q, et al. Wnt/beta-catenin-promoted macrophage alternative activation contributes to kidney fibrosis. J Am Soc Nephrol. 2018;29:182–93.
Chen Z, Sun J, Li T, Liu Y, Gao S, Zhi X, et al. Iron chelator-induced up-regulation of Ndrg1 inhibits proliferation and EMT process by targeting Wnt/beta-catenin pathway in colon cancer cells. Biochem Biophys Res Commun. 2018;506:114–21.
Zhang J, Cai H, Sun L, Zhan P, Chen M, Zhang F, et al. LGR5, a novel functional glioma stem cell marker, promotes EMT by activating the Wnt/beta-catenin pathway and predicts poor survival of glioma patients. J Exp Clin Cancer Res. 2018;37:225.
Chi B, Wang S, Bi S, Qin W, Wu D, Luo Z, et al. Effects of ganoderic acid A on lipopolysaccharide-induced proinflammatory cytokine release from primary mouse microglia cultures. Exp Ther Med. 2018;15:847–53.
Chang Y, Kong R. Ganoderic acid A alleviates hypoxia-induced apoptosis, autophagy, and inflammation in rat neural stem cells through the PI3K/AKT/mTOR pathways. Phytother Res. 2019;33:1448–56.
Ai J, Nie J, He J, Guo Q, Li M, Lei Y, et al. GQ5 hinders renal fibrosis in obstructive nephropathy by selectively inhibiting TGF-beta-induced smad3 phosphorylation. J Am Soc Nephrol. 2015;26:1827–38.
Wang W, Huang XR, Li AG, Liu F, Li JH, Truong LD, et al. Signaling mechanism of TGF-beta1 in prevention of renal inflammation: role of Smad7. J Am Soc Nephrol. 2005;16:1371–83.
Liu Y. Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol. 2004;15:1–12.
Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Investig. 2003;112:1776–84.
Rastaldi MP. Epithelial-mesenchymal transition and its implications for the development of renal tubulointerstitial fibrosis. J Nephrol. 2006;19:407–12.
Liu Y. New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol. 2010;21:212–22.
Lovisa S, LeBleu VS, Tampe B, Sugimoto H, Vadnagara K, Carstens JL, et al. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med. 2015;21:998–1009.
Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12:325–38.
Sato M, Muragaki Y, Saika S, Roberts AB, Ooshima A. Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Investig. 2003;112:1486–94.
Li Y, Shen Y, Li M, Su D, Xu W, Liang X, et al. Inhibitory effects of peroxisome proliferator-activated receptor gamma agonists on collagen IV production in podocytes. Mol Cell Biochem. 2015;405:233–41.
Rhyu DY, Yang Y, Ha H, Lee GT, Song JS, Uh ST, et al. Role of reactive oxygen species in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells. J Am Soc Nephrol. 2005;16:667–75.
Thornton TM, Pedraza-Alva G, Deng B, Wood CD, Aronshtam A, Clements JL, et al. Phosphorylation by p38 MAPK as an alternative pathway for GSK3 beta inactivation. Science. 2008;320:667–70.
Ellenrieder V, Hendler SF, Boeck W, Seufferlein T, Menke A, Ruhland C, et al. Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res. 2001;61:4222–8.
Lv ZM, Wang Q, Wan Q, Lin JG, Hu MS, Liu YX, et al. The role of the p38 MAPK signaling pathway in high glucose-induced epithelial-mesenchymal transition of cultured human renal tubular epithelial cells. PLoS One. 2011;6:e22806.
Pat B, Yang T, Kong C, Watters D, Johnson DW, Gobe G. Activation of ERK in renal fibrosis after unilateral ureteral obstruction: modulation by antioxidants. Kidney Int. 2005;67:931–43.
Li Z, Liu X, Wang B, Nie Y, Wen J, Wang Q, et al. Pirfenidone suppresses MAPK signalling pathway to reverse epithelial-mesenchymal transition and renal fibrosis. Nephrology. 2017;22:589–97.
Pardali E, Sanchez-Duffhues G, Gomez-Puerto MC, Ten Dijke P. TGF-beta-induced endothelial-mesenchymal transition in fibrotic diseases. Int J Mol Sci. 2017;18:2157.
Syed V. TGF-beta signaling in cancer. J Cell Biochem. 2016;117:1279–87.
MacFarlane EG, Haupt J, Dietz HC, Shore EM. TGF-beta family signaling in connective tissue and skeletal diseases. CSH Perspect Biol. 2017;9:a022269.
Radwan FF, Hossain A, God JM, Leaphart N, Elvington M, Nagarkatti M, et al. Reduction of myeloid-derived suppressor cells and lymphoma growth by a natural triterpenoid. J Cell Biochem. 2015;116:102–14.
Das A, Miller R, Lee P, Holden CA, Lindhorst SM, Jaboin J, et al. A novel component from citrus, ginger, and mushroom family exhibits antitumor activity on human meningioma cells through suppressing the Wnt/beta-catenin signaling pathway. Tumor Biol. 2015;36:7027–34.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (grants 81620108029, 81330074, 81261160507, 81974083, 81170632 and 81770738) and the Beijing Natural Science Foundation (grant 7172113).
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XQG and BXY designed the research. XQG, AM, JZH, YLJ, LW, GYS, ML, and JHR performed the research. XQG, JHR, and SQL analyzed the data. XQG and BXY wrote the manuscript. HZ and BXY revised the manuscript.
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Geng, Xq., Ma, A., He, Jz. et al. Ganoderic acid hinders renal fibrosis via suppressing the TGF-β/Smad and MAPK signaling pathways. Acta Pharmacol Sin 41, 670–677 (2020). https://doi.org/10.1038/s41401-019-0324-7
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DOI: https://doi.org/10.1038/s41401-019-0324-7
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